CA2024046A1 - Stabilized leukocyte-interferons - Google Patents
Stabilized leukocyte-interferonsInfo
- Publication number
- CA2024046A1 CA2024046A1 CA002024046A CA2024046A CA2024046A1 CA 2024046 A1 CA2024046 A1 CA 2024046A1 CA 002024046 A CA002024046 A CA 002024046A CA 2024046 A CA2024046 A CA 2024046A CA 2024046 A1 CA2024046 A1 CA 2024046A1
- Authority
- CA
- Canada
- Prior art keywords
- composition according
- vol
- ifn
- alpha
- interferon
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
- A61K38/212—IFN-alpha
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Dermatology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Abstract The stabilization of human interferon with disaccharides and optionally bile acids or bile acid derivatives.
Description
2 ~
The pcesent invention is concerned with the stabilization of l~u~vcyte interferon (IFN-a), ; 5 especially in the form of lyophiliza~es, using ; disa~(harides and opti.onally bile acids or bile acid derivatives.
Under IFN-a thece is to be undHr~tood a body--specific pro~;e;n having antiviral and immunoregulatory ~t~livity. The antiviral effect is acli~i.eved not by a direct i.n~luence on the viruses themselves, but by an activity on thei.c target cells in the sense of a protecti.on against the viral. infection. In addition to the ctntiviral 1~ ac~i.vL~y, a-interferon c~trl exert objectifiable effects on cancer tumors, which makes it suitable for use in cancer ~:herapy, and it in~luences ~he immune system of the body in that e.g. it activa~es macrophages and Nl~ cells ~nd increases the exere6sion of various immunologically si.gnificant cons~.l.uents of the cell membrane.
Thank6 to recombinarlt D~A technology, IFN- can today be preeared in a microbiological lllarlner ;.n amounts which hltherto could not be made available by isolation : 25 ~rom natural material (leucocytes, lym~hocytes) and ptlrification in ~pite of the greatest efforts.
~, This new technology has opened for the f i.c~t time a w~y ~or the intensive clinical testing and possible wide therapelltic use o~ IFN-~ and has made posr,ible an adequate supply o~ the acl.;.ve sub~l:ance for persons r3e~3~1ng a treatmerll, with ~,he acti.ve sllb~tctnce.
Ar/5.7.90 ; ! i, ~ ~
: . , , ' ' . , ', , ,. , ' . '. :,~ ', " , ~ r ~2~0~
I~ has now emerged that IFN-a in pure form is not completely stable ~ind suffers loss of its biological aotivity ducing stocage.
Diffecent adjuvants have therefore already been ll~ied for the stabilization o~ IFN-a. A certain ~itabilization of IFN-a has been ~t~hieved by the addil;ion of glycine (r,ee e.g. publ. PCT Application 86/00531 and European Patent, Publ. No. 82 481), whereby, however, albumin is prefeeably simultaneously added.
In efforts to achie~e a good stabilization of XFN-a over the longest possible period while avoiding the use of high-molecular compounds such a6 ~;e~rum albumin, gelatine, dextean or starch derivatives, it has bet?n found that this is successful using d;saccharides and optionally bil~e acids oe bile acid tleriva~ives.
The presen~ invention is accordingly o~oncecned with composition~ ;pecially in ~he form of lyophilizates, whi~h ~on~ain a disacchacide and optionally bile acids or bile acid derivatives, a~ well as a process for their manufao~ re which compcises treating an IFN-a solution with a disaccharide and optionally bile at~id~ oc bile acid derivatives and, if desired, lyophilizing the sollltion obtained. The eresen~ invention is al~io concerned with phaemaceutisal preparations based on the compositions in accordance with the invention as well as the use of disaccharides and optionally bile aoid~ or bile acid derivatives foc the ~itabiliza~ion of IFN-.
The composition6 in accordtlrlce wil;h the inverltion can be uned for the manlJfacturt? of a ph.lrmaceutical ~ceparation foe the theea~y or proptlylaxis o~ a lacge 3j5 numbec of in~ections and immunoregulatoey anomalies, especially neoplasms.
, ' ~: . ;:
: .
The pcesent invention is concerned with the stabilization of l~u~vcyte interferon (IFN-a), ; 5 especially in the form of lyophiliza~es, using ; disa~(harides and opti.onally bile acids or bile acid derivatives.
Under IFN-a thece is to be undHr~tood a body--specific pro~;e;n having antiviral and immunoregulatory ~t~livity. The antiviral effect is acli~i.eved not by a direct i.n~luence on the viruses themselves, but by an activity on thei.c target cells in the sense of a protecti.on against the viral. infection. In addition to the ctntiviral 1~ ac~i.vL~y, a-interferon c~trl exert objectifiable effects on cancer tumors, which makes it suitable for use in cancer ~:herapy, and it in~luences ~he immune system of the body in that e.g. it activa~es macrophages and Nl~ cells ~nd increases the exere6sion of various immunologically si.gnificant cons~.l.uents of the cell membrane.
Thank6 to recombinarlt D~A technology, IFN- can today be preeared in a microbiological lllarlner ;.n amounts which hltherto could not be made available by isolation : 25 ~rom natural material (leucocytes, lym~hocytes) and ptlrification in ~pite of the greatest efforts.
~, This new technology has opened for the f i.c~t time a w~y ~or the intensive clinical testing and possible wide therapelltic use o~ IFN-~ and has made posr,ible an adequate supply o~ the acl.;.ve sub~l:ance for persons r3e~3~1ng a treatmerll, with ~,he acti.ve sllb~tctnce.
Ar/5.7.90 ; ! i, ~ ~
: . , , ' ' . , ', , ,. , ' . '. :,~ ', " , ~ r ~2~0~
I~ has now emerged that IFN-a in pure form is not completely stable ~ind suffers loss of its biological aotivity ducing stocage.
Diffecent adjuvants have therefore already been ll~ied for the stabilization o~ IFN-a. A certain ~itabilization of IFN-a has been ~t~hieved by the addil;ion of glycine (r,ee e.g. publ. PCT Application 86/00531 and European Patent, Publ. No. 82 481), whereby, however, albumin is prefeeably simultaneously added.
In efforts to achie~e a good stabilization of XFN-a over the longest possible period while avoiding the use of high-molecular compounds such a6 ~;e~rum albumin, gelatine, dextean or starch derivatives, it has bet?n found that this is successful using d;saccharides and optionally bil~e acids oe bile acid tleriva~ives.
The presen~ invention is accordingly o~oncecned with composition~ ;pecially in ~he form of lyophilizates, whi~h ~on~ain a disacchacide and optionally bile acids or bile acid derivatives, a~ well as a process for their manufao~ re which compcises treating an IFN-a solution with a disaccharide and optionally bile at~id~ oc bile acid derivatives and, if desired, lyophilizing the sollltion obtained. The eresen~ invention is al~io concerned with phaemaceutisal preparations based on the compositions in accordance with the invention as well as the use of disaccharides and optionally bile aoid~ or bile acid derivatives foc the ~itabiliza~ion of IFN-.
The composition6 in accordtlrlce wil;h the inverltion can be uned for the manlJfacturt? of a ph.lrmaceutical ~ceparation foe the theea~y or proptlylaxis o~ a lacge 3j5 numbec of in~ections and immunoregulatoey anomalies, especially neoplasms.
, ' ~: . ;:
: .
- 3 - 2~ 6 The stabilization can be applied to natural oc cecombinant IFN-a (r-IFN-). Recomhinant IFN-aA
(r-IFN-~A) is an c~pecially pceferr~d IFN-~ in connection with the present invention. The content of IFN-a in the compositions in accordance with the inverltion is not critical. The concentral:ion range ex~ends ov~c mor~ than the power of ten and is limited at the uppee end ~;sentially only by the ~olubility of IFN-a.
Irl the ca~.e of human IFN-a ~:he~e come into consideration, foc example, concHrl~:cations up to 5~lO8 international units (I.U.)/ml, with a preferred range being 0.l x lO to l x lO I.U.fml, especially l x LO to 5 x lO I.U./ml.
The di~accharide, p~eferably lacto6e or sa~harose, is added ~o the IFN-~ so1llt:ion in a concentration of 0.5%
to L5% (wt./vol.), preferabl~ 5% (wt./vol.).
The bile acids or ~he bile acid deri~atives can be e.g. cholic acid, deoxycholic acid, glycodeoxycholic acid, taucodeoxycholic acid, chenodeoxycholic acid, glycoc~l~nodeoxycholic acid, taurochenodeoxycholic acid, glycocholic acid or tallrocholic acid, wi~ih glycocholic acid being especially preeerred. Tt is a~ded to the IFN-a solution in a concentration Oe O.Ol to 3%
(wt./vol.), preEerably 0.5~ (wt./vol.).
Further adjuvants for the pH-adjustment, e.g. NaOH, pH-buffering, e.g. ~hosphate bu~fer and citrate hu~fer, isotonization, e.g. sodium chloeide, and preservation of ~he ~ceyar-a~lon, e.g. me~hyl p-hydroxybenzoate an~ propyl p-hydroxybenzoate, a~ well a6 Eor strengthening the structure oE the lyophiliz-l~e, e.g. glyrine, can also be added.
Particular~ of the invention are described in the Eollowirlg ~xamples.
,; : ," ~ ,, ;.
.. : , :, , . ~ ,,.
2 ~
The r-IF~-A used in the Example6 can be ob~ained in pure form according to known pcocedures de~cribed in the lite~ature or according to procedu~e~ obvious to a per60n skilled in the art.
In order to determine the antiviral activity of the r-IFN-aA, there was used a cytopathological te~t with MDBK
(Madison Darby Bovine Kidney) cells and VSV (ve~icular stomatiti6 virus) viruses, ~hich has been described by Rubins~ein e~ al. [J. Virol. 37, 755-758 (1981)]. MDBK
cells and VSV viruses are gene~ally acce6~ible and can be obtained e.g. from the American ~ype Culture Collection (ATCC) (MDBK: ATCC Nos. CCL 21 and CRL 6071: VSV: ATCC
No. VR-1 59).
For the stability testing, solutions with r-IFN-aA
and the additives under inve~tigation were lyophilized and stored at different temperature~ (5, 25~, 35, 45, 55 and 65C). After fixed time interval6 the antiviral activity of the IFN-aA still pre~en~ in the lyophilizates was determined.
The following Examples illustrate the invention without limitin~ it.
ExamPle 1 3 mio. I.U. of r-IFN-aA were taken up in 1 ml of water containing hu~an ~erum albumin, glycine or lacto6e and optionally furthec adjuvants ~see Table 1). The solutions obtained were sterile-filteced (membrane filter, 0.~ ~m poce size) and loa~ed in 10 ml glass vials in a 3r steam-sterilized freeze-dryer. After free2ing the solutions at -40C during 4 h the primary drying of the lyophilization proce~s wa~ carried at about -30C under a prefisurQ of 0.1 mbar during lg h. Subsequen~ly, the : .:- . , ., ' :, ' : : ' : . , `~, ;:'~ ' -: :. .
~ ~2 ~
secondary drying was carried out under a full vacuum at ~20C during about 4 h. The glass vials were closed wi~h suitable aluminium caps in the freeze-dryer under a N2 atmosphere. They weEe subsequently subjected to diffeLen~ ::
stability tests, the results of which ace compiled in Table 1.
: - : .: i : . . . .
;, i .,,., . . , , ~ . ,.
~: , . -:, ;, ~
, Table 1 ComPoSitlOn of the lyoPhilizates containinq ~-IFN-aA
Ly~philizate from:
r-IFN-aA (mio. I.U.) 3.0 3.0 3.0 3.0 3.0 Sodium chloride (mg) g.o 10 xuman ~erum albumin (mg) 5.0 Mannitol pyrogen-fcee (mg~ - 20.0 Glycine (mg) - 20~0 ~ lOoO
Lactose (mg) - - 50.0 - - -NaH2P4 H20 a p q.s. - - q.s.
15 NaOH lN ad pH 7.4 - -q. 6 . q . ~ . _ Water for injec~ion 1.0 ml 1.0 ml 1.0 ~1 1.0 ml 1.0 ml An~tiviral ac_ivity (in mio. I.U.) after manufacture of the 3.0 3.0 Z.7 3.3 Z.3 lyophilizate 2 weeks/ 5C 3.2 3.0 2.8 3.3 1.8 " /25C 3.2 2.7 3.4 3.1 1.5 25" /35C 3.3 2.8 3.3 2.7 1.2 " /45C 2.7 2.0 3.0 2.9 O.9 " /55C 2.8 1.5 2.4 2.1 O.B
" ~65C Z.l O.S - - 0.4 3 month~ 5C 2.7 2.5 3.0 3.6 " /25C 2.5 2.3 ~.1 3.2 " /3SC 2.4 2.1 3.1 2.7 --5C 1.7 1.2 2.8 1.3 6 months/ 5C 3.5 3.1 3.2 3.1 " /25~C 3.3 3.1 3.2 2.~ -" /35C 2.6 1.9 3.0 2.~ -" /45C ~.t. 1.7 3.0 1.1 , ,, , . . .
. . . -.'-. ~ ." ',- ' : ''. ,:
. ., - .
2~2~
12months/ 5C 3 . 7 rl. t . 3 . 0 2 . ~ -" J25C 2.9 n.t. 2.9 2.5 " /35C 2.1 n.t. 2.7 1.3 - .
" /45C n. t . n. S . 2 . 7 1. 6 n. t . = not te~ted q . s . = guantum ~atis ~' ;' ~ , :
~ 35 .
2~240~
The best results were achieved with the lactose--containing lyophilizate (see column 3). This preparation exhibited an outstanding stability even after long-term stocage at the stocage temperature of 45C. which is almost prohibitive for IFN-a. ~his result could also be confirmed unequivocally in experiments with lyophilizates containing 1 mio. I.U. of ~-IFN-a~ ~see Table 2).
.
,, " :' ::' :` ' , ~ ,, .~ ~ ,. .
... , :
~ '; ;~ , . :
`` 2 ~2 ~
g Table 2 5 Composition of the lYoPhilizates con~ainina r-IFN-aA
Lyo~hilization from:
10 r-IFN-aA ~mio. I .U. ) O. S 0. 5 Glycine (mg) 10 . O - ~:
Lactose (mg) - 50. 0 NaOH lN ad pH 7.4q.6. 9.S. .
Water for injection 1.0 ml 1.0 ml :~
Ant_iral activity (in mio. I.U. ) afte~
manuf acture of the lyophiliza~e 0.4 0.4 2 week~/ 5C û. 5 0 . 4 " t25C o . ~ o. 4 " /35C O . ~ O . 4 " /45C 0. 3 O. 3 " /65C: O . 2 O. 3 3 month~J 5C 0. 5 O. 5 " /25~ 0.4 0.4 " /35C O . 3 0 . 4 " /45C O . 2 0 . 4 6 mon~h~/ 5C 0. 4 O. S
" /25C o . 4 o . ~
" /3~oC 0. 2 0 . 4 " /45C O . 05 0 . 3 2 ~
~xam~le 2 The stability o~ lyophilizates containing r-IFN-aA
and sacchaeose was investigated in an analogou& mannee to Example 1. It was established that the s~abilization of r-lFN-aA obtained with lacto~e can also be achieved with saccharose (see Table 3).
-- . ; . , :
. . , . ~ .
:, , :. , . . : :.
, ......... : ,.. .. :: : , .
: ~
:: : . , . . : . :
.: . .. :
2~2~
Table 3 Com~osition of the lyo~hilizates containinq r-IFN-aA
I.Yophilizate flom:
r-IFN-aA tmio. I.U.~ 3 3 3 10 Sodium chloride (mg~ 9.0 Human seru~ albumin 5.0 - -Glycine - 20.0 10.0 Saccharose (mg) - - - 50.0 NaHzPO4 H20 ad pH 7.4 - q-S-15 NaOH lN ad pH 7.4 _ q~s Water for injection ad 1. 0 ml1. 0 ml1. 0 20 Antiviral activit~
(in mio. I.U.~ after manuSacsure of the lyophilizate 2.7 3.0 3.4 3 month6~ 5C 2.7 2.5 3.9 " /25C 2.5 2.3 3.6 " /35C 2.4 2.1 3.7 " /45C 1.7 1.2 6 months/ 5C 3.5 3.1 4.0 " /25C 3.3 3.1 3.7 " /35~C ~.6 l.g 3.7 ' /45C - 1.7 7, ~
Exam le 3 The stability of lyophilizates containing r-IPM-aA
in high concentrations and lactose or saccharose was investigated in an analogous manner to Example 1. It was established ~ha~ the stabilization oE IFN-a produced using disaccharides can also be achile~ed in the ca~e of high rIFN-aA concentrat:ions (see Table 4).
:;
~' ' .
.' , ;
; .. ~ . . , . . , . .. .. ~ :,~ , "
2~24~
Table 4 Composition of l~oPhili-zate~ containinq r-IFN-aA
Lyophilized from: 1 2 3 4 r-IFN-aA ~mio. I.U.)9.0 9.0 18.0 18.0 Lacto~e 50,0 m5 - 50.0 mg Saccharo~e - 50.0 mg - 50.0 mg Glycine 10.0 mg 10.0 mg 10.0 mg 10.0 mg NaOH 1~ ad pH 7.4 - - - q.s.
Water for injection ad 1.0 ml 1.0 ml 1.0 ml 1.0 ml Antiviral activit~
(in ~iQ. I.~.) af~er manufacture of the lyophiliæate 8.~ 8.9 18.3 19.9 3 month~/ 5C 9.9 9.6 17.8 Z3.4 " /25C 10.0 10.5 19.1 23.Z
" /35C 10.3 10.1 20.5 n.t.
" /45C 10.4 10.9 22.0 n.t.
6 months/ 5C 9.7 n.t. 17.B 19.1 " /25C 9.9 n.t. 21.1 21.g /35C 8.g n.t. 16.6 n.t.
" /45C 8.4 n.t. 16.1 n.~.
: . , . ~ , . . ,, ; .~ :
~:. -- ., - . - . , : , - . . . .
2~2~6 Exam~e 4 The stability o~ lyophilizate6 containing ~-IFN-aA, lactQse and glycocholic acid was investigated in an analogous mann~c to Example 1. The results obtained a~e compiled in Table S.
:
2~
~, Table 5 Compo~ll.;on of the lyophilizates containinq r-IFN-aA `-lyophilizate from:
r-IFN-a~ (mio. I.U.j 1 3 g 18 Glycocholic acid (mg) 5.0 5.0 5.0 5.0 Lactose (mg) 50.050.0 50.0 50.0 10 Sodillm chloride (mg) Z.5 2.5 Z.5 2.5 NaOH lN ad ~H 7.4 q.~.q.s. q.6. q.6.
Water for injeo-ti.on ad 1.0 ml 1.0 ml 1.0 ml 1.0 ml An~iviral activity (in mio, I.U.~ after manufacture of the 20 lyo~hilizate 0.962.97 8.56 18.8 14 dayst 5C 0.85 " / RT 0.92 - - -" /35C 0.85 " /45C 0.83 6 months/ 5C 1.022.89 9.2 18.7 / RT 1.12.8Z 8.7 18.7 " /35C 1.06 3.11 8.9 18.3 30 " /45C 0.99 Z.71 8.94 n.t.
. : . . . . .
:
(r-IFN-~A) is an c~pecially pceferr~d IFN-~ in connection with the present invention. The content of IFN-a in the compositions in accordance with the inverltion is not critical. The concentral:ion range ex~ends ov~c mor~ than the power of ten and is limited at the uppee end ~;sentially only by the ~olubility of IFN-a.
Irl the ca~.e of human IFN-a ~:he~e come into consideration, foc example, concHrl~:cations up to 5~lO8 international units (I.U.)/ml, with a preferred range being 0.l x lO to l x lO I.U.fml, especially l x LO to 5 x lO I.U./ml.
The di~accharide, p~eferably lacto6e or sa~harose, is added ~o the IFN-~ so1llt:ion in a concentration of 0.5%
to L5% (wt./vol.), preferabl~ 5% (wt./vol.).
The bile acids or ~he bile acid deri~atives can be e.g. cholic acid, deoxycholic acid, glycodeoxycholic acid, taucodeoxycholic acid, chenodeoxycholic acid, glycoc~l~nodeoxycholic acid, taurochenodeoxycholic acid, glycocholic acid or tallrocholic acid, wi~ih glycocholic acid being especially preeerred. Tt is a~ded to the IFN-a solution in a concentration Oe O.Ol to 3%
(wt./vol.), preEerably 0.5~ (wt./vol.).
Further adjuvants for the pH-adjustment, e.g. NaOH, pH-buffering, e.g. ~hosphate bu~fer and citrate hu~fer, isotonization, e.g. sodium chloeide, and preservation of ~he ~ceyar-a~lon, e.g. me~hyl p-hydroxybenzoate an~ propyl p-hydroxybenzoate, a~ well a6 Eor strengthening the structure oE the lyophiliz-l~e, e.g. glyrine, can also be added.
Particular~ of the invention are described in the Eollowirlg ~xamples.
,; : ," ~ ,, ;.
.. : , :, , . ~ ,,.
2 ~
The r-IF~-A used in the Example6 can be ob~ained in pure form according to known pcocedures de~cribed in the lite~ature or according to procedu~e~ obvious to a per60n skilled in the art.
In order to determine the antiviral activity of the r-IFN-aA, there was used a cytopathological te~t with MDBK
(Madison Darby Bovine Kidney) cells and VSV (ve~icular stomatiti6 virus) viruses, ~hich has been described by Rubins~ein e~ al. [J. Virol. 37, 755-758 (1981)]. MDBK
cells and VSV viruses are gene~ally acce6~ible and can be obtained e.g. from the American ~ype Culture Collection (ATCC) (MDBK: ATCC Nos. CCL 21 and CRL 6071: VSV: ATCC
No. VR-1 59).
For the stability testing, solutions with r-IFN-aA
and the additives under inve~tigation were lyophilized and stored at different temperature~ (5, 25~, 35, 45, 55 and 65C). After fixed time interval6 the antiviral activity of the IFN-aA still pre~en~ in the lyophilizates was determined.
The following Examples illustrate the invention without limitin~ it.
ExamPle 1 3 mio. I.U. of r-IFN-aA were taken up in 1 ml of water containing hu~an ~erum albumin, glycine or lacto6e and optionally furthec adjuvants ~see Table 1). The solutions obtained were sterile-filteced (membrane filter, 0.~ ~m poce size) and loa~ed in 10 ml glass vials in a 3r steam-sterilized freeze-dryer. After free2ing the solutions at -40C during 4 h the primary drying of the lyophilization proce~s wa~ carried at about -30C under a prefisurQ of 0.1 mbar during lg h. Subsequen~ly, the : .:- . , ., ' :, ' : : ' : . , `~, ;:'~ ' -: :. .
~ ~2 ~
secondary drying was carried out under a full vacuum at ~20C during about 4 h. The glass vials were closed wi~h suitable aluminium caps in the freeze-dryer under a N2 atmosphere. They weEe subsequently subjected to diffeLen~ ::
stability tests, the results of which ace compiled in Table 1.
: - : .: i : . . . .
;, i .,,., . . , , ~ . ,.
~: , . -:, ;, ~
, Table 1 ComPoSitlOn of the lyoPhilizates containinq ~-IFN-aA
Ly~philizate from:
r-IFN-aA (mio. I.U.) 3.0 3.0 3.0 3.0 3.0 Sodium chloride (mg) g.o 10 xuman ~erum albumin (mg) 5.0 Mannitol pyrogen-fcee (mg~ - 20.0 Glycine (mg) - 20~0 ~ lOoO
Lactose (mg) - - 50.0 - - -NaH2P4 H20 a p q.s. - - q.s.
15 NaOH lN ad pH 7.4 - -q. 6 . q . ~ . _ Water for injec~ion 1.0 ml 1.0 ml 1.0 ~1 1.0 ml 1.0 ml An~tiviral ac_ivity (in mio. I.U.) after manufacture of the 3.0 3.0 Z.7 3.3 Z.3 lyophilizate 2 weeks/ 5C 3.2 3.0 2.8 3.3 1.8 " /25C 3.2 2.7 3.4 3.1 1.5 25" /35C 3.3 2.8 3.3 2.7 1.2 " /45C 2.7 2.0 3.0 2.9 O.9 " /55C 2.8 1.5 2.4 2.1 O.B
" ~65C Z.l O.S - - 0.4 3 month~ 5C 2.7 2.5 3.0 3.6 " /25C 2.5 2.3 ~.1 3.2 " /3SC 2.4 2.1 3.1 2.7 --5C 1.7 1.2 2.8 1.3 6 months/ 5C 3.5 3.1 3.2 3.1 " /25~C 3.3 3.1 3.2 2.~ -" /35C 2.6 1.9 3.0 2.~ -" /45C ~.t. 1.7 3.0 1.1 , ,, , . . .
. . . -.'-. ~ ." ',- ' : ''. ,:
. ., - .
2~2~
12months/ 5C 3 . 7 rl. t . 3 . 0 2 . ~ -" J25C 2.9 n.t. 2.9 2.5 " /35C 2.1 n.t. 2.7 1.3 - .
" /45C n. t . n. S . 2 . 7 1. 6 n. t . = not te~ted q . s . = guantum ~atis ~' ;' ~ , :
~ 35 .
2~240~
The best results were achieved with the lactose--containing lyophilizate (see column 3). This preparation exhibited an outstanding stability even after long-term stocage at the stocage temperature of 45C. which is almost prohibitive for IFN-a. ~his result could also be confirmed unequivocally in experiments with lyophilizates containing 1 mio. I.U. of ~-IFN-a~ ~see Table 2).
.
,, " :' ::' :` ' , ~ ,, .~ ~ ,. .
... , :
~ '; ;~ , . :
`` 2 ~2 ~
g Table 2 5 Composition of the lYoPhilizates con~ainina r-IFN-aA
Lyo~hilization from:
10 r-IFN-aA ~mio. I .U. ) O. S 0. 5 Glycine (mg) 10 . O - ~:
Lactose (mg) - 50. 0 NaOH lN ad pH 7.4q.6. 9.S. .
Water for injection 1.0 ml 1.0 ml :~
Ant_iral activity (in mio. I.U. ) afte~
manuf acture of the lyophiliza~e 0.4 0.4 2 week~/ 5C û. 5 0 . 4 " t25C o . ~ o. 4 " /35C O . ~ O . 4 " /45C 0. 3 O. 3 " /65C: O . 2 O. 3 3 month~J 5C 0. 5 O. 5 " /25~ 0.4 0.4 " /35C O . 3 0 . 4 " /45C O . 2 0 . 4 6 mon~h~/ 5C 0. 4 O. S
" /25C o . 4 o . ~
" /3~oC 0. 2 0 . 4 " /45C O . 05 0 . 3 2 ~
~xam~le 2 The stability o~ lyophilizates containing r-IFN-aA
and sacchaeose was investigated in an analogou& mannee to Example 1. It was established that the s~abilization of r-lFN-aA obtained with lacto~e can also be achieved with saccharose (see Table 3).
-- . ; . , :
. . , . ~ .
:, , :. , . . : :.
, ......... : ,.. .. :: : , .
: ~
:: : . , . . : . :
.: . .. :
2~2~
Table 3 Com~osition of the lyo~hilizates containinq r-IFN-aA
I.Yophilizate flom:
r-IFN-aA tmio. I.U.~ 3 3 3 10 Sodium chloride (mg~ 9.0 Human seru~ albumin 5.0 - -Glycine - 20.0 10.0 Saccharose (mg) - - - 50.0 NaHzPO4 H20 ad pH 7.4 - q-S-15 NaOH lN ad pH 7.4 _ q~s Water for injection ad 1. 0 ml1. 0 ml1. 0 20 Antiviral activit~
(in mio. I.U.~ after manuSacsure of the lyophilizate 2.7 3.0 3.4 3 month6~ 5C 2.7 2.5 3.9 " /25C 2.5 2.3 3.6 " /35C 2.4 2.1 3.7 " /45C 1.7 1.2 6 months/ 5C 3.5 3.1 4.0 " /25C 3.3 3.1 3.7 " /35~C ~.6 l.g 3.7 ' /45C - 1.7 7, ~
Exam le 3 The stability of lyophilizates containing r-IPM-aA
in high concentrations and lactose or saccharose was investigated in an analogous manner to Example 1. It was established ~ha~ the stabilization oE IFN-a produced using disaccharides can also be achile~ed in the ca~e of high rIFN-aA concentrat:ions (see Table 4).
:;
~' ' .
.' , ;
; .. ~ . . , . . , . .. .. ~ :,~ , "
2~24~
Table 4 Composition of l~oPhili-zate~ containinq r-IFN-aA
Lyophilized from: 1 2 3 4 r-IFN-aA ~mio. I.U.)9.0 9.0 18.0 18.0 Lacto~e 50,0 m5 - 50.0 mg Saccharo~e - 50.0 mg - 50.0 mg Glycine 10.0 mg 10.0 mg 10.0 mg 10.0 mg NaOH 1~ ad pH 7.4 - - - q.s.
Water for injection ad 1.0 ml 1.0 ml 1.0 ml 1.0 ml Antiviral activit~
(in ~iQ. I.~.) af~er manufacture of the lyophiliæate 8.~ 8.9 18.3 19.9 3 month~/ 5C 9.9 9.6 17.8 Z3.4 " /25C 10.0 10.5 19.1 23.Z
" /35C 10.3 10.1 20.5 n.t.
" /45C 10.4 10.9 22.0 n.t.
6 months/ 5C 9.7 n.t. 17.B 19.1 " /25C 9.9 n.t. 21.1 21.g /35C 8.g n.t. 16.6 n.t.
" /45C 8.4 n.t. 16.1 n.~.
: . , . ~ , . . ,, ; .~ :
~:. -- ., - . - . , : , - . . . .
2~2~6 Exam~e 4 The stability o~ lyophilizate6 containing ~-IFN-aA, lactQse and glycocholic acid was investigated in an analogous mann~c to Example 1. The results obtained a~e compiled in Table S.
:
2~
~, Table 5 Compo~ll.;on of the lyophilizates containinq r-IFN-aA `-lyophilizate from:
r-IFN-a~ (mio. I.U.j 1 3 g 18 Glycocholic acid (mg) 5.0 5.0 5.0 5.0 Lactose (mg) 50.050.0 50.0 50.0 10 Sodillm chloride (mg) Z.5 2.5 Z.5 2.5 NaOH lN ad ~H 7.4 q.~.q.s. q.6. q.6.
Water for injeo-ti.on ad 1.0 ml 1.0 ml 1.0 ml 1.0 ml An~iviral activity (in mio, I.U.~ after manufacture of the 20 lyo~hilizate 0.962.97 8.56 18.8 14 dayst 5C 0.85 " / RT 0.92 - - -" /35C 0.85 " /45C 0.83 6 months/ 5C 1.022.89 9.2 18.7 / RT 1.12.8Z 8.7 18.7 " /35C 1.06 3.11 8.9 18.3 30 " /45C 0.99 Z.71 8.94 n.t.
. : . . . . .
:
Claims (21)
1. A composition containing .alpha.- interferon, a disaccharide and optionally bile acids or bile acid derivatives.
2. A composition according to claim 1, wherein the .alpha.-interferon is a natural or a recombinant human leucocyte interferon.
3. A composition according to claim 2, which contains r-IFN-.alpha.A.
4. A composition according to any one of claims 1 to 3 in the form of a lyophilizate.
5. A composition according to any one of claims 1 to 4, wherein the disacchacide is lactose or saccharose.
6. A composition according to any one of claims 1 to 5, which contains 0.5% to 15% (wt./vol.) of lactose or saccharose.
7. A composition according to any one of claims 1 to 5, which contains 5% (wt./vol.) of lactose or saccharose.
8. A composition according to any one of claims 1 to 6, which contains 0.01% to 3.0% (wt./vol.) of bile acids or bile acid derivatives, preferably 0.1% to 1.0% (wt.
vol.) of glycocholic acid.
vol.) of glycocholic acid.
9. A composition according to any one of claims 1 to 6, which contains 0.5% (wt./vol.) of bile acid derrivatives, preferably 0.5% (wt./vol.) of glycocholic
10. A composition containing r-IFN-.alpha.A, 5%
(wt./vol.) of lactose and 0.5% (wt./vol.) of glycocholic acid.
(wt./vol.) of lactose and 0.5% (wt./vol.) of glycocholic acid.
11. A composition according to any one of claims 1-10 as a pharmaceutically active material.
12. A composition according to any one of claims 1-10 as an antivirally and immunoregulatory active material.
13. A process for the manufacture of a composition according to any one of claims 1 to 10, which process comprises treating .alpha.-interferon with a disaccharide and optionally bile acids or bile acid derivatives, preferably glycocholic acid, and, if desired, lyophilizing the solution obtained.
14. Pharmaceutical preparations based on a composition according to any one of claims 1 to 10.
15. The use of disaccharides and optionally bile acids or bile acid derivatives, preferably glycocholic acid, for the stabilization of .alpha.-interferon.
16. The use of a composition according to ally one of claims 1-10 for the manufacture of a pharmaceutical preparation for the therapy or prophylaxis of illnesses.
17. The use of a composition according to any one of claims 1-10 for the manufacture of a pharmaceutical preparation for the therapy or prophylaxis of viral infections.
18. The use of a composition according to any one of claims 1-10 for the manufacture of a pharmaceutical preparation for the therapy or prophylaxis of immuno-regulatory anomalies.
19. The use of a composition according to any one of claims 1-10 for the manufacture of a pharmaceutical preparation for the therapy or prophylaxis of neoplasms.
20. A composition containing .alpha.-interferon, a disaccharide and optionally bile acids or bile acid derivatives prepared according to a process as claimed in claim 13.
21. The invention substantially as hereinbefore described, especially with reference to the examples.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH3514/89 | 1989-09-28 | ||
CH351489 | 1989-09-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2024046A1 true CA2024046A1 (en) | 1991-03-29 |
Family
ID=4257630
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002024046A Abandoned CA2024046A1 (en) | 1989-09-28 | 1990-08-27 | Stabilized leukocyte-interferons |
Country Status (26)
Country | Link |
---|---|
EP (1) | EP0420049B1 (en) |
JP (1) | JPH03130232A (en) |
KR (1) | KR910005886A (en) |
CN (1) | CN1050503A (en) |
AR (1) | AR244551A1 (en) |
AT (1) | ATE92334T1 (en) |
AU (1) | AU636653B2 (en) |
CA (1) | CA2024046A1 (en) |
CZ (1) | CZ277712B6 (en) |
DD (1) | DD298054A5 (en) |
DE (1) | DE59002183D1 (en) |
FI (1) | FI904756A0 (en) |
HU (1) | HU205555B (en) |
IE (1) | IE903479A1 (en) |
IL (1) | IL95769A0 (en) |
IS (1) | IS3631A7 (en) |
MC (1) | MC2149A1 (en) |
MX (1) | MX22522A (en) |
MY (1) | MY106615A (en) |
NO (1) | NO904218L (en) |
NZ (1) | NZ235153A (en) |
PH (1) | PH27531A (en) |
PT (1) | PT95454A (en) |
RU (1) | RU2008017C1 (en) |
YU (1) | YU184090A (en) |
ZA (1) | ZA907579B (en) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU6794194A (en) * | 1993-05-18 | 1994-12-20 | Bukh Meditec A/S | A method for the preparation of interferons |
WO1997041885A1 (en) * | 1996-05-09 | 1997-11-13 | Feronpatent Limited | Stabilization of interferons in aqueous solution for manufacture of sublingually administered tablets |
JP2001526662A (en) * | 1997-05-09 | 2001-12-18 | フェロンパテント リミテッド | Stabilization of interferon in aqueous solution for the production of sublingual tablets |
SK285284B6 (en) * | 1998-03-26 | 2006-10-05 | Schering Corporation | Aqueous formulation permitting stabilization of PEG-interferon alpha conjugates, method for producing a lyophilized powder and article of manufacture comprising thereof |
US6180096B1 (en) | 1998-03-26 | 2001-01-30 | Schering Corporation | Formulations for protection of peg-interferon alpha conjugates |
CN1175901C (en) * | 1999-12-06 | 2004-11-17 | 天津华立达生物工程有限公司 | Stable water solution of interferon |
CN101039660B (en) | 2004-08-12 | 2010-10-06 | 先灵公司 | Stable pegylated interferon formulation |
DE102004048379A1 (en) | 2004-10-01 | 2006-04-13 | "Stiftung Caesar" (Center Of Advanced European Studies And Research) | Spring element made of sputtered shape memory alloy |
CU23432B6 (en) * | 2005-11-02 | 2009-10-16 | Ct Ingenieria Genetica Biotech | STABILIZED FORMULATIONS CONTAINING GAMMA AND ALFA INTERFERONS IN POTENTIAL PROPORTIONS |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5821691A (en) * | 1981-07-29 | 1983-02-08 | Mochida Pharmaceut Co Ltd | Purifying method of interferon |
EP0080879B1 (en) * | 1981-11-28 | 1986-10-01 | Sunstar Kabushiki Kaisha | Pharmaceutical composition containing interferon in stable state |
ATE31023T1 (en) * | 1983-04-28 | 1987-12-15 | Armour Pharma | PHARMACEUTICAL PREPARATION CONTAINING PURIFIED FIBRINONECTIN. |
DE3484374D1 (en) * | 1983-08-04 | 1991-05-08 | Green Cross Corp | GAMMA INTERFERON COMPOSITION. |
AU592552B2 (en) * | 1985-03-25 | 1990-01-18 | Schering Corporation | Stable gamma interferon formulation |
US4816568A (en) * | 1986-05-16 | 1989-03-28 | International Minerals & Chemical Corp. | Stabilization of growth hormones |
-
1990
- 1990-08-27 CA CA002024046A patent/CA2024046A1/en not_active Abandoned
- 1990-09-03 NZ NZ235153A patent/NZ235153A/en unknown
- 1990-09-06 CZ CS904328A patent/CZ277712B6/en unknown
- 1990-09-20 DE DE9090118132T patent/DE59002183D1/en not_active Expired - Fee Related
- 1990-09-20 AT AT90118132T patent/ATE92334T1/en not_active IP Right Cessation
- 1990-09-20 EP EP90118132A patent/EP0420049B1/en not_active Expired - Lifetime
- 1990-09-21 ZA ZA907579A patent/ZA907579B/en unknown
- 1990-09-21 AU AU63098/90A patent/AU636653B2/en not_active Expired - Fee Related
- 1990-09-24 MC MC902149A patent/MC2149A1/en unknown
- 1990-09-24 MX MX2252290A patent/MX22522A/en unknown
- 1990-09-24 HU HU906021A patent/HU205555B/en not_active IP Right Cessation
- 1990-09-25 IL IL95769A patent/IL95769A0/en unknown
- 1990-09-26 DD DD90344228A patent/DD298054A5/en not_active IP Right Cessation
- 1990-09-26 PH PH41267A patent/PH27531A/en unknown
- 1990-09-26 MY MYPI90001656A patent/MY106615A/en unknown
- 1990-09-26 AR AR90317958A patent/AR244551A1/en active
- 1990-09-27 IE IE347990A patent/IE903479A1/en unknown
- 1990-09-27 NO NO90904218A patent/NO904218L/en unknown
- 1990-09-27 IS IS3631A patent/IS3631A7/en unknown
- 1990-09-27 CN CN90108133A patent/CN1050503A/en active Pending
- 1990-09-27 RU SU904831274A patent/RU2008017C1/en active
- 1990-09-27 PT PT95454A patent/PT95454A/en not_active Application Discontinuation
- 1990-09-27 JP JP2258806A patent/JPH03130232A/en active Pending
- 1990-09-27 FI FI904756A patent/FI904756A0/en not_active IP Right Cessation
- 1990-09-27 KR KR1019900015368A patent/KR910005886A/en not_active Application Discontinuation
- 1990-09-28 YU YU184090A patent/YU184090A/en unknown
Also Published As
Publication number | Publication date |
---|---|
CZ277712B6 (en) | 1993-03-17 |
MY106615A (en) | 1995-06-30 |
EP0420049B1 (en) | 1993-08-04 |
MX22522A (en) | 1993-10-01 |
EP0420049A1 (en) | 1991-04-03 |
HUT56284A (en) | 1991-08-28 |
DD298054A5 (en) | 1992-02-06 |
IE903479A1 (en) | 1991-04-10 |
FI904756A0 (en) | 1990-09-27 |
IL95769A0 (en) | 1991-06-30 |
KR910005886A (en) | 1991-04-27 |
MC2149A1 (en) | 1992-03-10 |
PH27531A (en) | 1993-08-18 |
HU906021D0 (en) | 1991-03-28 |
NO904218D0 (en) | 1990-09-27 |
NZ235153A (en) | 1993-03-26 |
DE59002183D1 (en) | 1993-09-09 |
RU2008017C1 (en) | 1994-02-28 |
AU636653B2 (en) | 1993-05-06 |
ZA907579B (en) | 1991-06-26 |
YU184090A (en) | 1992-09-07 |
ATE92334T1 (en) | 1993-08-15 |
AU6309890A (en) | 1991-04-11 |
NO904218L (en) | 1991-04-02 |
IS3631A7 (en) | 1991-03-29 |
CS432890A3 (en) | 1992-12-16 |
AR244551A1 (en) | 1993-11-30 |
PT95454A (en) | 1991-05-22 |
CN1050503A (en) | 1991-04-10 |
HU205555B (en) | 1992-05-28 |
JPH03130232A (en) | 1991-06-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4496537A (en) | Biologically stable alpha-interferon formulations | |
EP0130619B1 (en) | Hepatitis b vaccine and method for its preparation | |
KR950014915B1 (en) | Asialoglycoprotein-conjugated compounds | |
CA1254510A (en) | Fibronectin preparations | |
US4895716A (en) | Stabilized formulations of gamma interferons | |
RU2484847C2 (en) | Lyophilised formulation containing influenza vaccine, and method for preparing it | |
CA2024046A1 (en) | Stabilized leukocyte-interferons | |
US20160120946A1 (en) | Compositions comprising gc-macrophage activating factor and uses thereof | |
US20050163752A1 (en) | Human interferon-beta formulations | |
EP1066059B1 (en) | Formulations for protection of peg-interferon alpha conjugates | |
JPH01279843A (en) | Freeze-dried vaccine for hepatitis a | |
EP0329609A2 (en) | Antiviral combination | |
KR880002037B1 (en) | Interferon composition and its preparation method | |
Higgins et al. | Recombinant human interferon-γ as prophylaxis against rhinovirus colds in volunteers | |
CA1297788C (en) | Treatment of aids virus with recombinant human alpha interferon | |
US5165921A (en) | Method for treating condyloma acuminatum with interferon | |
EP0344643B1 (en) | Antiviral pharmaceutical composition | |
DE19700535C1 (en) | Use of polypeptide for treating liver diseases | |
JPS6293300A (en) | Interferon composition | |
JPS6222725A (en) | Medicine containing tnf as effective component | |
CN1660414A (en) | Stable preparation of interferon | |
KR20000010591A (en) | Stabilized tablet of anti-hepatitis type b | |
CA1295240C (en) | Biologically stable interferon compositions | |
Matsubara et al. | Rabbit Zosteriform Eruption Induced by Intra‐arterial Inoculation of Herpes Simplex Virus, Type 1 | |
TH2141A (en) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FZDE | Discontinued |